U.S. patent application number 11/660682 was filed with the patent office on 2008-02-07 for compositions and methods to lower glycohemoglobin levels.
Invention is credited to Mary C. Gannon, Frank Nuttall.
Application Number | 20080031925 11/660682 |
Document ID | / |
Family ID | 36000627 |
Filed Date | 2008-02-07 |
United States Patent
Application |
20080031925 |
Kind Code |
A1 |
Gannon; Mary C. ; et
al. |
February 7, 2008 |
Compositions and Methods to Lower Glycohemoglobin Levels
Abstract
The invention provides for a diet that significantly reduces the
glycohemoglobin levels in individuals with type 2 diabetes. A diet
plan can be provided to an individual in the form of cards and/or
pages with an appropriate meal plan, food items and/or pre-packaged
meals, or in an electronic medium for the individuals to use to
develop appropriate meal plans. The diet comprises food items
having a nutritional composition that consists essentially of 30%
protein, 50% fats, and 20% carbohydrates, or food items having a
nutritional composition that consists essentially of 30% protein,
40% fats, and 30% carbohydrates.
Inventors: |
Gannon; Mary C.; (Eagan,
MN) ; Nuttall; Frank; (Eagan, MN) |
Correspondence
Address: |
DINESH AGARWAL, P.C.
5350 SHAWNEE ROAD
SUITE 330
ALEXANDRIA
VA
22312
US
|
Family ID: |
36000627 |
Appl. No.: |
11/660682 |
Filed: |
August 25, 2005 |
PCT Filed: |
August 25, 2005 |
PCT NO: |
PCT/US05/30483 |
371 Date: |
February 21, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60604271 |
Aug 25, 2004 |
|
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|
Current U.S.
Class: |
424/439 ;
426/106; 702/19 |
Current CPC
Class: |
A23L 33/30 20160801;
A61P 3/10 20180101; A23L 33/40 20160801 |
Class at
Publication: |
424/439 ;
426/106; 702/019 |
International
Class: |
A61K 47/00 20060101
A61K047/00; A61P 3/10 20060101 A61P003/10; B65D 81/32 20060101
B65D081/32; G06F 19/00 20060101 G06F019/00 |
Claims
1. An article of manufacture, comprising food items for a single
meal or snack, wherein the food items have a nutritional
composition that consists essentially of 30% protein, 40% fats, and
30% carbohydrates.
2. The article of manufacture of claim 1, wherein the food items
are a pre-packaged meal.
3. The article of manufacture of claim 1, wherein the food items
are breakfast food items, lunch food items, dinner food items, or
snack food items.
4. An article of manufacture, comprising food items for a single
day, wherein the food items have a nutritional composition that
consists essentially of 30% protein, 40% fats, and 30%
carbohydrates.
5. The article of manufacture of claim 4, wherein the food items
comprise a breakfast meal, a lunch meal, and a dinner meal.
6. The article of manufacture of claim 5, wherein the food items
further comprise at least one snack.
7. The article of manufacture of claim 4, wherein caloric value of
the sum of the food items essentially equals the daily-recommended
caloric intake for an individual.
8. The article of manufacture of claim 4, wherein ingestion of such
food items, for a period of about 3 weeks, by an individual having
elevated glycohemoglobin levels, decreases glycohemoglobin levels
in the individual.
9. The article of manufacture of claim 8, wherein the decrease is
statistically significant.
10. An article of manufacture, comprising food items for multiple
days, wherein the food items have a nutritional composition that
consists essentially of 30% protein, 40% fats, and 30%
carbohydrates.
11. An article of manufacture comprising food items for multiple
days, wherein a portion of the food items have a nutritional
composition that consists essentially of 30% protein, 40% fats, and
30% carbohydrates, and wherein a portion of the food items have a
nutritional composition that consists essentially of 30% protein,
50% fats, and 20% carbohydrates.
12. A method of reducing the level of glycohemoglobin in an
individual, comprising: providing an article of manufacture,
wherein the article of manufacture comprises food items for a
single day, wherein the food items have a nutritional composition
that consists essentially of 30% protein, 40% fats, and 30%
carbohydrates, and instructing the individual to consume the food
items.
13. The method of claim 12, wherein the instructions are provided
online.
14. The method of claim 12, wherein the instructions are provided
as written instructions accompanying the article of
manufacture.
15. A method of developing a meal plan for an individual having
type 2 diabetes, comprising: providing the daily-recommended
caloric intake for an individual; and selecting food items for the
individual based on the individual's daily-recommended caloric
intake, wherein the food items have a nutritional composition that
consists essentially of 30% protein, 40% fats, and 30%
carbohydrates, thereby developing a meal plan for the
individual.
16. The method of claim 12 or 15, wherein ingestion of the food
items does not result in ketosis in the individual.
17. The method of claim 12 or 15, wherein ingestion of the food
items results in maintenance of the individual's weight.
18. The method of claim 12 or 15, wherein ingestion of the food
items does not result in the individual losing weight.
19. A method of developing a meal plan for an individual having
type 2 diabetes, comprising: providing the daily-recommended
caloric intake for an individual; and selecting food items for the
individual based on the individual's daily-recommended caloric
intake, wherein a portion of the food items have a nutritional
composition that consists essentially of 30% protein, 40% fats, and
30% carbohydrates, and wherein a portion of the food items have a
nutritional composition that consists essentially of 30% protein,
50% fats, and 20% carbohydrates.
20. A computer-readable storage medium having instructions stored
thereon for causing a programmable processor to: select a
combination of food items for at least one day, wherein the food
items collectively have a nutritional composition that consists
essentially of 30% protein, 40% fats, and 30% carbohydrates.
21. The computer-readable storage medium of claim 20, wherein a
desired number of meals and snacks per day is input into the
processor.
22. The computer-readable storage medium of claim 20, wherein the
weight and/or height of an individual is input into the
processor.
23. The computer-readable storage medium of claim 20, wherein the
daily caloric intake of an individual is input into the
processor.
24. The computer-readable storage medium of claim 20, wherein food
item likes and/or dislikes are input into the processor.
Description
TECHNICAL FIELD
[0001] This invention relates to glycohemoglobin levels, and more
particularly to a compositions and methods to lower glycohemoglobin
levels.
BACKGROUND
[0002] The glucose absorbed following the ingestion of
glucose-containing foods is largely responsible for a rise in the
circulating glucose concentration. Dietary proteins, fats, and
absorbed fructose and galactose resulting from the digestion of
sucrose and lactose, respectively, have little effect on blood
glucose concentration. Even short-term starvation (hours) results
in a dramatic decrease in the blood glucose concentration in people
with type 2 diabetes, which appears to be due largely to a rapid,
progressive decrease in the rate of glycogenolysis.
SUMMARY
[0003] The invention provides for diets that significantly reduce
the glycohemoglobin levels in individuals with type 2 diabetes. The
diets can be provided to an individual in the form of cards and/or
pages with an appropriate meal plan, food items and/or pre-packaged
meals, or in an electronic medium for the individuals to use to
develop appropriate meal plans. For example, one diet comprises
food items having a nutritional composition that consists
essentially of 30% protein, 50% fats, and 20% carbohydrates, while
another diet comprises food items having a nutritional composition
that consists essentially of 30% protein, 40% fats, and 30%
carbohydrates.
[0004] In one aspect, the invention provides an article of
manufacture that includes food items for a single meal or snack,
for a single day, or for multiple days. In one embodiment of the
invention, the food items have a nutritional composition that
consists essentially of 30% protein, 50% fats, and 20%
carbohydrates. Usually, the fats consist essentially of 10%
saturated fats and 40% mono- and poly-unsaturated fats. In another
embodiment, the food items have a nutritional composition that
consists essentially of 30% protein, 40% fats, and 30%
carbohydrates.
[0005] Generally, the food items can be breakfast food items, lunch
food items, dinner food items, and/or snack food items. In some
embodiments, the food items can be in a pre-packaged meal.
Typically, the caloric value of the sum of the food items
essentially equals the daily-recommended caloric intake for an
individual. According to the invention, ingestion of such food
items, for a period of about 3 weeks, by an individual having
elevated glycohemoglobin levels, decreases glycohemoglobin levels
in the individual. Such a decrease can be statistically
significant.
[0006] In another aspect, the invention provides an article of
manufacture that includes food items for multiple days. In one
embodiment of the invention, a portion of the food items have a
nutritional composition that consists essentially of 30% protein,
50% fats, and 20% carbohydrates and another portion of the food
items have a nutritional composition that consists essentially of
30% protein, 40% fats, and 30% carbohydrates. This combination of
diets can be further combined with food items that have a
nutritional composition that consists essentially of 30% protein,
30% fats, and 40% carbohydrates. Alternatively, a portion of the
food items have a nutritional composition that consists essentially
of 30% protein, 30% fats, and 40% carbohydrates while a portion of
the food items have a nutritional composition that consists
essentially of 30% protein, 50% fats, and 20% carbohydrates. As
another alternative, a portion of the food items have a nutritional
composition that consists essentially of 30% protein, 30% fats, and
40% carbohydrates while a portion of the food items have a
nutritional composition that consists essentially of 30% protein,
40% fats, and 30% carbohydrates.
[0007] In another aspect, the invention provides methods of
reducing the level of glycohemoglobin in an individual. Such a
method can include providing an article of manufacture that
includes food items for a single day that have a nutritional
composition that consists essentially of 30% protein, 50% fats, and
20% carbohydrates, and instructing the individual to consume the
food items. Such instructions can be provided online or as written
instructions accompanying the article of manufacture. Included in
such a method, or as a separate method of reducing the level of
glycohemoglobin in an individual, an article of manufacture can be
provided that includes food items for a single day that have a
nutritional composition that consists essentially of 30% protein,
40% fats, and 30% carbohydrates along with the appropriate
instructions.
[0008] In yet another aspect, the invention provides methods of
developing a meal plan for an individual having type 2 diabetes.
Such a method includes providing the daily-recommended caloric
intake for an individual; and selecting food items for the
individual based on the individual's daily-recommended caloric
intake. In an embodiment of the invention, the food items have a
nutritional composition that consists essentially of 30% protein,
50% fats, and 20% carbohydrates. In another embodiment of the
invention, the food items have a nutritional composition that
consists essentially of 30% protein, 40% fats, and 30%
carbohydrates.
[0009] Using these steps, a meal plan can be developed for the
individual. The embodiments described herein can be used in
combination. For example, one, two, or three weeks of food items
that have a nutritional composition that consists essentially of
30% protein, 50% fats, and 20% carbohydrates, followed by one, two,
or three weeks of food items that have a nutritional composition
that consists essentially of 30% protein, 40% fats, and 30%
carbohydrates.
[0010] According to the invention, ingestion of the food items does
not result in ketosis in the individual, and results in maintenance
of the individual's weight (i.e., does not result in the individual
losing weight).
[0011] In still another aspect, the invention provides methods of
developing a meal plan for an individual having type 2 diabetes.
Such a method includes providing the daily-recommended caloric
intake for an individual; and selecting food items for the
individual based on the individual's daily-recommended caloric
intake. In one embodiment of the invention, a portion of the food
items have a nutritional composition that consists essentially of
30% protein, 50% fats, and 20% carbohydrates, and a portion of the
food items have a nutritional composition that consists essentially
of 30% protein, 40% fats, and 30% carbohydrates and/or 30% protein,
30% fats, and 40% carbohydrates. In another embodiment of the
invention, a portion of the food items have a nutritional
composition that consists essentially of 30% protein, 40% fats, and
30% carbohydrates, and a portion of the food items have a
nutritional composition that consists essentially of 30% protein,
50% fats, and 20% carbohydrates and/or 30% protein, 30% fats, and
40% carbohydrates.
[0012] In yet another aspect, the invention provides a
computer-readable storage medium having instructions stored thereon
for causing a programmable processor to select a combination of
food items for at least one day, wherein the food items
collectively have a nutritional composition that consists
essentially of 30% protein, 50% fats, and 20% carbohydrates or
collectively have a nutritional composition that consists
essentially of 30% protein, 40% fats, and 30% carbohydrates. The
computer-readable storage medium, by instructing a programmable
processor, can also select food items for individual meals, meals
for a day or a number of days, or meals for one or more weeks that
alternate or change between the two nutritional compositions set
forth herein.
[0013] For example, a desired number of meals and snacks per day
can be input into the processor; the weight and/or height of an
individual can be input into the processor; the daily caloric
intake of an individual can be input into the processor; and/or
food item likes and/or dislikes can be input into the processor.
The output is then the meal plans as described above. The output
can be in any format including but not limited to print-outs,
e-mails, and hyperlinks. The output can include a list of food item
combinations for one or more meals or actual recipes for making
such food items.
[0014] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
invention, suitable methods and materials are described below. In
addition, the materials, methods, and examples are illustrative
only and not intended to be limiting. All publications, patent
applications, patents, and other references mentioned herein are
incorporated by reference in their entirety. In case of conflict,
the present specification, including definitions, will control.
[0015] The details of one or more embodiments of the invention are
set forth in the accompanying drawings and the description below.
Other features, objects, and advantages of the invention will be
apparent from the drawings and detailed description, and from the
claims.
DESCRIPTION OF DRAWINGS
[0016] FIG. 1 shows an example of instructions for a processor to
determine meal plans using the Diet.sub.20 of the invention.
[0017] FIG. 2 depicts graphs. FIG. 2A shows the mean body weight on
while on the control (open circles) or test diet (closed circles).
FIG. 2B shows the plasma beta-hydroxybutyrate concentration after 5
weeks on the control (open circles) or test diet (closed
circles).
[0018] FIG. 3 depicts graphs. FIG. 3A shows the mean plasma glucose
concentration before (open triangles) and after (open circles) 5
weeks on the control diet. Insert: Net and total 24 hour integrated
glucose area response. Area response was not significantly
different. FIG. 3B shows the mean plasma glucose concentration
before (closed triangles) and after (closed circles) 5 weeks on the
test diet. Insert: Net and total 24 hour integrated glucose area
response. Both the net and total area responses were significantly
lower after the test diet (p.ltoreq.0.05).
[0019] FIG. 4 depicts graphs. FIG. 4A shows the mean serum insulin
concentration before (open triangles) and after (open circles) 5
weeks on the control diet. Insert: Net and total 24 hour integrated
insulin area response. Area response was not significantly
different. FIG. 4B shows the mean serum insulin concentration
before (closed triangles) and after (closed circles) 5 weeks on the
test diet. Insert: Net and total 24 hour integrated insulin area
response. Both the net and total area responses were significantly
lower after the test diet (p.ltoreq.0.05).
[0020] FIG. 5 shows the mean total glycohemoglobin response during
the 5 weeks of the control (open circles) or test diet (closed
circles). The tGHb on the test diet was significantly lower at
weeks 3, 4, and 5 compared to the control diet (p.ltoreq.0.05).
[0021] FIG. 6 depicts graphs. FIG. 6A shows the mean plasma
glucagon concentration before (open triangles) and after (open
circles) 5 weeks on the control diet. Insert: Net and total 24 hour
integrated glucagon area response. Area response was not
significantly different. FIG. 6B shows the mean plasma glucagon
concentration before (closed triangles) and after (closed circles)
5 weeks on the test diet. Insert: Net and total 24 hour integrated
glucagon area response. The net and total area responses were
significantly higher after the test diet (p.ltoreq.0.05).
[0022] FIG. 7 depicts graphs. FIG. 7A shows the mean serum
triacylglycerol concentration before (open triangles) and after
(open circles) 5 weeks on the control diet. Insert: Net and total
24 hour integrated triacylglycerol area response. Area response was
not significantly different. FIG. 7B shows the mean serum
triacylglycerol concentration before (closed triangles) and after
(closed circles) 5 weeks on the test diet. Insert: Net and total 24
hour integrated triacylglycerol area response. The total area
response was significantly lower after the test diet
(p.ltoreq.0.05).
[0023] Like reference symbols in the various drawings indicate like
elements.
DETAILED DESCRIPTION
[0024] To determine whether or not a diet low in food-derived
glucose can lower both the fasting as well as the post-prandial
blood glucose, a low carbohydrate diet was designed in which
readily digestible starch-containing foods were de-emphasized. The
carbohydrate content in the diet, however, was sufficient to
prevent ketosis, which is in contrast to low-carbohydrate diets
that are often advocated for weight loss. Glycohemoglobin, 24-hour
glucose, insulin, C-peptide, beta-hydroxybutyrate, glucagon,
triacylglycerol, and non-esterified fatty acids (NEFA) were
examined to evaluate the effects of the diet on individuals with
type 2 diabetes.
Blood Glucose, Glycohemoglobin and Type II Diabetes
[0025] Blood glucose levels represent the amounts of sugars present
in the blood at the time the blood is withdrawn. Blood glucose
levels vary throughout the day and depend upon diet, exercise, and
the level of insulin in the blood. Individuals can test their own
blood glucose levels using, for example, a home monitor or a
hand-held meter.
[0026] The % total glycohemoglobin and the % hemoglobin A.sub.1c
are two methods used to measure the glucose attached to hemoglobin.
The % total glycohemoglobin used in this study is specific for the
ketoamine adduct resulting from glucose attachment to primary amino
groups on amino acids in the globin molecules in hemoglobin.
Normally, only a small percentage of hemoglobin in the blood
(.about.4% to 6%) has glucose bound to it. People with diabetes (or
other conditions that increase their blood glucose levels),
however, have a higher % glycohemoglobin than normal. The %
glycohemoglobin is considered to be an index of the average, i.e.
24-hour integrated blood glucose concentration over an extended
period of time, that of the life of the red blood cell (weeks to
months). Thus, the % glycohemoglobin level is considered to
represent the average blood glucose concentration in the weeks and
months preceding the test. The glycohemoglobin level does not
exhibit rapid changes due to exercise, medications, or eating prior
to the test.
[0027] Diabetes and some of the risks of developing complications
caused therefrom have been associated with the % glycohemoglobin.
Diabetes is a chronic disease that develops when either the
pancreas cannot produce enough insulin or the body cannot use
insulin properly. Insulin allows sugar (e.g., glucose) to enter
cells, where it is used for energy. Insulin also helps the body
store extra glucose in muscle, fat, and liver cells. Symptoms of
diabetes include increased thirst and frequent urination;
unexplained increase in appetite; unexplained weight loss; fatigue;
erection problems; blurred vision; and tingling or numbness in
hands or feet. Individuals with diabetes have an increased risk for
many serious health problems including hardening of the arteries
(atherosclerosis) and heart problems, eye problems than can lead to
blindness, circulation and nerve problems; and kidney disease or
kidney failure. Type 2 diabetes can develop at any age, although it
usually develops in adults. Type 2 diabetes used to be called
adult-onset diabetes, as well as non-insulin-dependent diabetes
mellitus (NIDDM) because it can often be treated without using
insulin.
Diets Resulting in Low Biologically-Available Glucose
[0028] It has been determined and is described herein that an
individuals' % glycohemoglobin level, plasma glucose level, serum
insulin concentration, serum C-peptide concentration, and serum
triacylglycerol level can be significantly reduced by following a
diet that consists essentially of food items having a nutritional
composition of approximately 30% protein, 50% fats, and 20%
carbohydrate. This diet is referred to herein as "Diet.sub.20."
Such levels also can be significantly reduced by following a diet
that consists essentially of food items having a nutritional
composition of approximately 30% protein, 40% fats, and 30%
carbohydrate. This diet is referred to herein as "Diet.sub.30."
[0029] The desired nutritional composition described herein for
Diet.sub.20 or Diet.sub.30 can be calculated for the meals in a
single day, the meals in multiple days, the meals in one week, or
longer. The diet of the invention usually uses the recommended
daily caloric intake of an individual and the desired distribution
of the food ingested in a day (e.g., the number of meals, and
snacks, if desired) to determine the amount of food that should be
ingested in each meal or snack in a day.
[0030] It may be impractical to achieve an exact percentage of each
nutritional component in a food item, meal, or other diet
constituent. It is understood by those of skill in the art that it
is easier to calculate the desired nutritional composition in meals
ingested over days or weeks than it is to calculate the desired
nutritional composition over a single meal or the meals ingested in
a single day. As such, it is to be understood that the percentage
of components disclosed herein represents approximations attainable
by a person of ordinary skill in the art using the nutritional
guidelines provided herein for each diet. In addition, the diet
provided herein may contain other components (e.g., nucleic acids,
and/or medicaments) provided that these other components do not
significantly alter the indicated nutritional composition of
proteins, fats, and carbohydrates. This is what is meant by
"consisting essentially of."
[0031] The Diet.sub.20 and Diet.sub.30 disclosed herein result in a
statistically significant reduction in, for example, an
individual's glycohemoglobin levels. As used herein, "statistically
significant" refers to a p-value of less than or equal to 0.05,
e.g., a p-value of less than or equal to 0.025 or a p-value of less
than or equal to 0.01, using an appropriate measure of statistical
significance, e.g., a two-tailed paired t-test.
[0032] A meal plan appropriately calculated for an individual using
the Diet.sub.20 or the Diet.sub.30 described herein can be provided
to an individual in need of such a diet in the form of cards or
pages. The cards or pages can provide a list of food items and
appropriate suggestions for meal combinations using such food
items. The cards or pages also can provide a meal plan (i.e.,
suggested combinations of food items and meals for a given day)
that meets both the caloric intake and nutritional composition
requirements over the desired number of days or weeks. Recommended
serving size can be indicated, and recipes for some of the food
items or meal combinations can be provided, if desired.
[0033] A meal plan appropriately calculated for an individual using
the Diet.sub.20 or the Diet.sub.30 disclosed herein also can be
provided to an individual in the form of actual food items or
pre-packaged meals. Food items can be packaged separately and
ingested individually or combined by the individual into meals. As
indicated above, suggestions for a variety of meals using
combinations of the food items and pre-packaged meals that
essentially meet the nutritional composition of the Diet.sub.20 or
Diet.sub.30 and the caloric intake and the eating preferences of
the individual can be provided. Pre-packaged meals are well known
in the art and are routinely used in many types of diets,
particularly those for the purpose of weight management. For
example, sufficient food items and/or pre-packaged meals for
multiple days (e.g., 7 days worth) or for one or more weeks (e.g.,
2 weeks worth, or 1 month worth) can be provided to an
individual.
[0034] In addition to the Diet.sub.20 and Diet.sub.30 disclosed
herein, additional diets are disclosed that allow for ingestion of
more carbohydrates and fewer fats, but that also reduce
glycohemoglobin levels in an individual with elevated levels. For
example, "Diet.sub.40" is a diet in which food items having a
nutritional composition that consists essentially of 30% protein,
30% fats, and 40% carbohydrates. Diet.sub.20, Diet.sub.30, and
Diet.sub.40 can be used in conjunction with one another (e.g.,
repeating schedule of 3-5 weeks on Diet.sub.20, 2-3 weeks on
Diet.sub.30, and 2-3 weeks on Diet.sub.40) to lower or maintain an
individual's glycohemoglobin levels while consistently providing
the individual with palatable and digestable food items and meals.
It is apparent to those of skill in this art that the diet regimen
an individual follows (e.g., which diet and for how long) will
depend, in part, on the individual's ability to manage
glycohemoglobin levels and/or the progression of the diabetes,
while still taking into account the lipid profile of the
individual.
Computer-Readable Medium for Implementing Diet.sub.20 or
Diet.sub.30
[0035] In addition to the cards, pages, recipes, meal plans, food
items, and/or pre-packaged meals discussed above, the Diet.sub.20
or Diet.sub.30 described herein can be provided to an individual in
the form of a computer-readable medium that contains instructions
for causing a programmable processor to generate a meal plan for an
individual that follows the Diet.sub.20 or Diet.sub.30. For
example, a computer-readable medium containing instructions for
generating a meal plan according to Diet.sub.20 or Diet.sub.30 can
be provided to an individual in the form of, without limitation, a
floppy disk, a CD, or a DVD. In addition, a computer-readable
medium of the invention can be accessed electronically using, for
example, a dial-up or internet connection to download or use
remotely. FIG. 1 shows a chart of a representative processing
system that can be used with a computer-readable medium of the
invention to generate a meal plan according to the Diet.sub.20
disclosed herein.
[0036] Instructions carried on a computer-readable medium of the
invention can be implemented in a high level procedural or object
oriented programming language to communicate with a processor.
Alternatively, such instructions can be implemented in assembly or
machine language, which can be compiled or interpreted. A processor
can be a computer such as a personal computer or workstation that
executes program code. One or more input devices (e.g., a keyboard
or a mouse) and one or more output devices (e.g., a printer or a
monitor) can be used in addition to the processor.
[0037] For example, an individual (or a representative of the
individual, e.g., a nurse, a nutritionist, a dietician, etc.) can
input the height (in inches and/or centimeters) and weight (in
pounds and/or kilograms) of the individual. Age and gender also can
be input, but are not necessary. The daily caloric intake can take
into account an individual's activity level and/or weight goals,
although neither the Diet.sub.20 nor the Diet.sub.30 described
herein are intended for weight loss purposes. For example,
individuals can indicate if they consider themselves to be
sedentary, or to have minimal, moderate, or strenuous activity
during the day, and whether they wish to maintain their weight,
lose weight, or gain weight. From this information, an individual's
recommended daily caloric intake can be determined. Alternatively,
a desired daily caloric intake, if known, can be input
directly.
[0038] The individual then can input the number of meals they wish
to ingest in a day. Some individuals prefer to eat three meals a
day, while others prefer to include snacks between one or more
meals. The preference for the number of meals and snacks in a day
can be used to determine the caloric distribution during the
day.
[0039] The instructions contained on a computer-readable medium of
the invention also can allow for a variety of specialized options.
For example, individuals can select (or de-select) food items that
the individual likes or dislikes, or cannot eat, for example, due
to allergies, religious beliefs/practices, or adverse reactions
with a medication. The instructions contained on a
computer-readable medium of the invention can include a system of
equivalents such that foods that are removed due to, for example,
one of the previously-discussed reasons, can be substituted with
food items having a similar caloric and nutritional value as the
food removed. In addition, the instructions on the
computer-readable medium can allow for input of the number of
people for which a recipe will be prepared, the time frame for
which the individual wants to spend preparing a food item, and/or a
choice of the ethnicity of a food item or meal (e.g., Chinese,
Italian, or Mexican).
[0040] As part of the invention, there is provided a database
containing the nutritional composition of a variety of food items
and meals. Such a database can be contained on the same or on a
different computer-readable medium as the instructions for
determining the Diet.sub.20 or Diet.sub.30 meal plan, or can be
accessed and/or downloaded via, for example, an internet
connection. The database provides a large number of food items and
meals that can be mixed and matched in combination to result in a
variety of meals and snacks having the appropriate nutritional
composition and caloric values.
[0041] In accordance with the present invention, there may be
employed conventional laboratory and/or clinical testing techniques
within the skill of the art. Such techniques are explained fully in
the literature. The invention will be further described in the
following examples, which do not limit the scope of the invention
described in the claims.
EXAMPLES
A. Diet.sub.20
Example 1
Participants
[0042] Male subjects with mild, untreated type 2 diabetes were
studied in a "Special Diagnostic and Treatment Unit" (SDTU), a
facility similar to a Clinical Research Center. All subjects met
the National Diabetes Data Group criteria for the diagnosis of type
2 diabetes mellitus (Report of the Expert Committee on the
Diagnosis and Classification of Diabetes Mellitus: Diab. Care,
21:S5-S19 (Suppl 11), 1998). Subject characteristics are given in
Table 1. The study was approved by the Department of Veterans
Affairs Medical Center and the University of Minnesota Committees
on Human Subjects and written informed consent was obtained from
all subjects. The subjects did not have hematologic abnormalities,
kidney disease, liver disease, macroalbuminuria (>300 mg/24 h),
congestive heart failure, or untreated thyroid disease. Prior to
the study, all subjects were interviewed to determine their
physical activity profile, food aversions, and to explain the study
process and commitment in detail. Subjects confirmed they had been
weight stable for at least 3 months. They were instructed to
maintain their current activity level throughout the study. Two
weeks prior to beginning the study, the subjects completed a 3-day
food frequency questionnaire with one of the days being a Saturday
or Sunday. This information was used to calculate the total food
energy necessary to maintain body weight. None of the subjects was
being treated with oral hypoglycemic agents or insulin at the time
they were enrolled in the study. A 5-week randomized, crossover
study design was used with a 5-week washout period between diets.
TABLE-US-00001 TABLE 1 Patient characteristics Duration Height
Weight of Age [inches [pounds BMI tGHb diabetes Concomitant Patient
(yrs) (cm)] (kg)] (kg/m.sup.2) (%) (months) diseases Medications 1
69 74 221 27 8.7 60 hypertension, simvastatin, (188) (100)
dyslipidemia, lisinopril, coronary rabeprazole, heart disease ASA 2
72 69 239 35 10.0 12 chronic terazosin (165) (109) obstructive
pulmonary disease 3 51 68 181 27 8.6 12 none ASA, (173) (82)
naproxen 4 66 72 196 27 9.0 180 hypertension none (183) (89) 5 82
71 204 28 11.2 48 none lisinopril, (180) (93) ASA 6 56 72 267 35
10.1 24 obesity, none (183) (121) dyslipidemia 7 51 66 195 31 10.0
14 none ASA, (168) (89) naproxen 8 59 67 233 36 9.4 19
hypertension, lisinopril (170) (106) obesity Mean 63.3 70 217 31
9.6 46 -- -- (176) (99) Range 51-82 66-74 181-267 27-36 8.6-11.2
12-180 -- -- (168-188) (82-121)
Example 2
Diet
[0043] The control diet was designed according to the
recommendations of the American Heart Association (American Heart
Association: Dietary guidelines for healthy American adults; a
statement for physicians and health professionals by the Nutrition
Committee, Circulation, 74: 1465A-1468A, 1986), and the United
States Department of Agriculture (USDA: The food guide pyramid,
Washington D.C., US Government Printing Office, 1992; USDA & US
Department of Health and Human Services: Nutrition and your health:
dietary guidelines for Americans, Washington D.C., US Government
Printing Office, 1995). The control diet consisted of 55%
carbohydrate, with an emphasis on starch-containing foods, 15%
protein, and 30% fat (10% monounsaturated, 10% polyunsaturated, 10%
saturated fatty acid content). The control diet is a diet that is
recommended for the general population as a means of reducing one's
risk for coronary heart disease.
[0044] The low-biologically-available-glucose diet (the "test"
diet) was designed to have a nutritional composition that consists
essentially of 30% protein, 50% fats, and 20% carbohydrate. The
saturated fatty acid content of the test diet was .about.10% of
total food energy, thus the majority of the fat was mono- and
polyunsaturated fats. The nutritional composition of the control
and test diets is given in Table 2, and Table 3 shows
representative meals for the control and test diet. TABLE-US-00002
TABLE 2 Composition of diets Control Diet Test Diet Energy (kcal)
2,825 2,825 Protein [g (%)] 106 (15) 210 (30) Carbohydrate [g (%)]
388 (55) 142 (20) Monosaccharides (g) 64 31 Disaccharides (g) 50 16
Fat [g (%)] 94 (30) 158 (50) Monounsaturated (g) 29 62
Polyunsaturated (g) 24 35 Saturated (g) 33 30 Cholesterol (mg) 375
441 Dietary fiber (g) 24 36
[0045] TABLE-US-00003 TABLE 3 Sample Menu for One Day Control
Diet.sub.20 Breakfast 57 g (2 oz) Total Cereal Breakfast 124 g (4
oz) Egg Substitute 50 g (2 slice) Wheat Bread 23 g Green Pepper 244
g (1 Cup) 2% Milk 56 g (2 oz) Cheddar Cheese 10 g (2 tsp) Margarine
18 g (1 slice) Tomato 10 g (2 tsp) Jelly 131 g (1) Fresh Orange 114
g (1) Banana 120 g (4 oz) grape Jelly 8 g (2 tsp) Sugar Lunch 50 g
(2 slices) Wheat Bread Lunch 226 g (8 oz) Roasted Ham (3 oz)Lean
Ham 85 g (3 oz) Swiss Cheese 5 g (1 Tsp) Mustard 90 g (1 Small)
Tomato (2 oz) Lite Cheese 28 g (2 Tbsp) Mayonnaise 10 g (2 Tsp)
Margarine 5 g (1 Tsp) Mustard 5 g (1) Radish 7 g Lettuce Leaves 36
g (4) Carrot Sticks 253 g (1 Cup) Split Pea Soup 50 g (4) Celery
Sticks 20 g (3) Rye Krisp 166 g (1) Fresh Pear 21 g (7) Vanilla
Wafers Snack 72 g (30) Grapes Snack None 58 g (1) Banana Nut Muffin
5 g (1 Tsp) Margarine Dinner 135 g (1 Cup) Green Beans Dinner 50 g
(1/2 Stalk) Raw Celery Sticks 25 g (1 slice) Wheat Bread 170 g (6
oz) Tuna 15 g(1 Tbsp) Margarine 55 g (4 Tbsp) Mayonnaise 138 g
(1)Apple 80 g (1/2 Cup) Peas 28 g (2) Fig Newtons 138 g (1) Raw
Apple 41 g (3/4 Cup) Lettuce 45 g (1/2) Tom) Tomato Wedges 15 g (1
Tbsp) Reg Italian Dressing 113 g (4 oz) Lean Pork Roast 160 g (1
Cup) Cooked Noodles Snack 57 g (2 oz) American Cheese Snack 56 g (2
oz) Dry Roasted Peanuts 17 g (6) Saltine Crackers
[0046] The distribution of total food energy intake for the control
diet was about: 24% for breakfast, 27% for lunch, 9% for the
1600-hour snack, 32% for supper, and 8% for the 2100-hour snack.
For the Diet.sub.20, the distribution was about: 17% for breakfast,
38% for lunch, 32% for supper, and 12% for the 2100-hour snack. The
amount of carbohydrate in the meals and snacks for the control diet
was approximately 113 g for breakfast, 79 g for lunch, 38 g for the
1600-hour snack, 109 g for dinner and 34 g for the 2100-hour snack
(total of 373 g CHO); for the Diet.sub.20, it was approximately 25
g for breakfast, 53 g for lunch, 42 g for dinner and 21 g for the
2100-hour snack (total of 141 g CHO).
Example 3
Experimental Plan
[0047] Subjects were randomized to begin the study with either the
test diet or the control diet by a flip of a coin. Six subjects
started on the test diet, five subjects started on the control
diet. Unfortunately, three of the subjects started on the control
diet did not complete the study for personal reasons. Therefore,
the data are presented on 8 subjects who completed both arms of the
study. Subjects were admitted to the SDTU on the evening prior to
the study. The following day, standardized meals containing 55%
carbohydrate, 30% fat, and 15% protein (essentially the same as the
control diet) were given to all subjects for breakfast, lunch and
dinner, at 0800 h, 1200 h, and 1800 h. Subjects were asked to
remain in the SDTU during the study period with minimal
activity.
[0048] On the second day in the SDTU, standardized meals again were
given. This diet was similar for both baseline studies and was
referred to as "pre-control" and "pre-test" diets depending on
which study diet followed the inpatient stay. In addition to the
0800 h, 1200 h and 1800 h meals; snacks were given at 1600 h and
2100 h. Blood was obtained fasting at 0730 h, 0745 h and 0800 h,
every 15 minutes for the first hour after meals, every 1/2-hour for
the next two hours, and then hourly until the next meal. Blood was
drawn at a total of 46 time points. Following this 24-hour data
accumulation period, the subjects were sent home with all the
necessary food for the next 2-3 days as appropriate for the diet to
which they were randomized.
[0049] Subjects returned to the SDTU every 2-3 days to pick up food
and meet with the study dietitian. At that time, subjects provided
a urine specimen for analysis of creatinine and urea to determine
dietary compliance. Subjects were weighed and had blood pressure,
total glycohemoglobin, and blood glucose measured. If their body
weight decreased or increased on two successive occasions, the
total food energy of the meals was increased or decreased as
appropriate to attempt to maintain weight stability throughout the
study. In addition, subjects were interviewed regarding dietary
compliance, and questions or concerns about the study. At the end
of the 5-week period, the subjects again were admitted to the SDTU
and blood was drawn over a 24-hour period of time as described
above. During this time, the test or control meals were continued
for each appropriate group. Following this 24-hour data
accumulation period, the subjects were sent home to consume a diet
of their choice, i.e., their usual diet, for the following .about.5
weeks. This was the washout period.
Example 4
Biological Measurements
[0050] The plasma glucose concentration and beta-hydroxybutyrate
concentration were determined by enzymatic methods using an Analox
analyzer with an O.sub.2 electrode (Analox Instruments, Ltd;
London, UK). Total glycohemoglobin was measured by boronate
affinity HPLC (BioRad Variant, BioRad Labs, Inc.; Hercules,
Calif.). Serum immunoreactive insulin was measured using a standard
double-antibody radioimmunoassay (RIA) method using kits produced
by Incstar (Stillwater, Minn.). Glucagon and C-peptide were
measured by RIA using kits from Linco Research (St. Louis, Mo.) and
Diasorin (Stillwater, Minn.), respectively. NEFAs were measured
enzymically using a kit manufactured by Wako Chemicals, Inc.
(Richmond, Va.). Weight was determined in street clothes without
shoes on a digital scale (Scalitronix, White Plains, N.Y.). Blood
pressure was measured using a Dinemap instrument (Critikon/Mediq,
Pennsauken, N.J.).
[0051] The total .alpha.-amino nitrogen concentration was
determined by the method of Goodwin, which is a measure of the
total amino acid concentration. The plasma TSH (Abbott Architect;
Abbott Park, Ill.), GH (Quest; New Brighton, Minn.), B12 and folate
(Diagnostic Products Corp.; Los Angeles, Calif.) were determined by
chemiluminescence. Total T3 and free T4 were determined by
Chemiflex (Abbott Architect). IGF-1 was determined by RIA (Quest).
Homocysteine was measured by HPLC (Hewlett Packard, Palo Alto,
Calif.). The plasma and urine creatinine, urea nitrogen and uric
acid were measured by an automated method on an OrthoClinical
diagnostic Vitros 950 analyzer (Raritan, N.J.). Microalbumin was
determined using a Beckinan-Coulter array 360 analyzer (Fullerton,
Calif.). Urinary free cortisol was determined in the laboratory of
Dr. B. Pearson-Murphy using an HPLC purification step followed by a
cortisol binding assay. Urinary aldosterone was determined by RIA
(Diagnostic Products Corp.). Urinary calcium and magnesium were
measured colorimetrically on a J&J Vitros Instrument (J&J
Engineering; Poulsbo, Wash.). Qualitative urinary ketones were
measured with a Ketostix (Bayer Corporation; Elkhart, Ind.).
[0052] The total amount of protein oxidized was determined by
quantifying the urine urea nitrogen excreted over the 24 hours of
the study in association with the change in the amount of urea
nitrogen retained endogenously. The latter was calculated by
determining the change in plasma urea nitrogen concentration
between the fasting baseline and at the end of the 24-hour study
period, and correcting for plasma water by dividing by 0.94. In
this calculation, it is assumed that there is a relatively rapid
and complete equilibration of urea in total body water. Total body
water as a percentage of body weight was calculated as previously
described (Watson et al., 1980, Am. J. Clin. Nutr., 33:27-39). The
overall assumption is that a change in plasma urea concentration is
indicative of a corresponding change in total body water urea
concentration. In this 24-hour study, the beginning and ending urea
nitrogen concentrations were essentially identical, indicating no
retention of urea. The sum of total urea nitrogen in urine and body
water was divided by 0.86 to account for 14% lost to metabolism in
the gut.
[0053] The net 24-hour incremental area responses were calculated
using the overnight fasting value as baseline. Total 24-hour area
responses were calculated using zero as the baseline. Both area
calculations were done using a computer program based on the
trapezoid rule. Statistics were determined using Student's t test
for paired variates, with the Statview 512+ program (Brain Power,
Calabasas, Calif.) for the Macintosh computer (Apple Computer,
Cupertino, Calif.). A p value of <0.05 was the criterion for
significance. Data are presented as the mean.+-.SEM, unless
otherwise indicated.
Example 5
Results #1
[0054] The average body weight was 219.+-.10 lbs (99.+-.4.5 kg) and
216.+-.10 lbs (98.+-.4.5 kg) at the beginning of the control and
test diets, respectively. At the end of the 5 weeks on the control
diet, the average body weight was 215.+-.10 lbs (98.+-.4.5 kg).
Following 5 weeks on the test diet, the average weight was 212.+-.9
lbs (96.+-.4.1 kg). Thus, the average body weight decreased by 4
pounds (1.8 kg) during the 5-week study period, regardless of diet
(FIG. 2A).
[0055] Urine ketones were monitored twice weekly while subjects
were on the test diet. They were always zero to trace using
nitroprusside impregnated Ketostix (Bayer Corporation, Elkhart,
Ind.). Twenty-four hour urine ketones were identical at the
beginning and end of the test diet (196.+-.8 .mu.mol/L and 196.+-.9
.mu.mol/L respectively). Before and after the control diet, they
were 187.+-.7 .mu.mol/L and 203.+-.10 .mu.mol/L, respectively.
[0056] The mean fasting .beta.-hydroxybutyrate concentration was
225.+-.15 .mu.mol/L after five weeks on the control diet (FIG. 2B).
Following five weeks on the test diet, the mean fasting
concentration was 236.+-.27 .mu.mol/L. The 24-hour profiles were
similar when the subjects ingested either the control or the test
diet.
[0057] The mean fasting glucose concentration prior to starting the
control diet was 180.+-.10 mg/dl (10.+-.0.6 mmol/L) (FIG. 3A).
After five weeks on the control diet, the fasting glucose
concentration was decreased to 159.+-.11 mg/dl (8.8.+-.0.6 mmol/L),
but this was not significant (p=0.66). Prior to starting the test
diet the mean fasting glucose concentration was 167.+-.13 mg/dl
(9.3.+-.0.7 mmol/L), similar to that prior to starting the control
diet (p=0.24). After 5 weeks on the test diet, the fasting glucose
concentration was significantly decreased to 119.+-.7 mg/dl
(66.+-.0.4 mmol/L) (p<0.003) (FIG. 3B).
[0058] The mean 24-hour integrated net glucose area responses were
similar for the pre-control, pre-test and post-control diets
(681.+-.174, 731.+-.159 and 730.+-.236 mgh/dl [38.+-.9.7,
41.+-.8.8, 41.+-.13.1 mmolhr/L], respectively) (FIG. 3, insets,
left bars). Following five weeks on the test diet, the net mean
24-hour integrated glucose area response was decreased by 77%
(165.+-.59 mgh/dl) (9.2.+-.3.3 mmolhr/L) p<0.02).
[0059] Total 24-hour integrated glucose area responses also were
similar for pre-control, pre-test and post-control diets
(4998.+-.337, 4746.+-.301 and 4554.+-.347 mgh/dl [278.+-.18.7,
264.+-.16.7, 253.+-.19.3 mmolhr/L], respectively) (FIG. 3, insets,
right bars). The total area response following 5 weeks on the test
diet was decreased significantly (3023.+-.160 mgh/dl) (168.+-.8.9
mmolhr/L) (p<0.0004 compared to the 5-week post-control and
p<0.0001 compared to pre-test). Based on these integrated areas,
the mean glucose concentration over the 24 hour periods of study
was reduced from 198 mg/dl to 126 mg/dl (11 mmol/L to 7 mmol/L)
after 5 weeks on the test diet, a 36% decrease (p<0.0001).
[0060] The mean fasting insulin concentrations before and after 5
weeks on both the control and test diets were identical (12.+-.2
.mu.U/ml) (72.+-.12 pmol/L) (FIGS. 4A and 4B).
[0061] The mean 24-hour integrated insulin area response above the
fasting value was similar following the pre- and post-control diet
and pre-test diet (534.+-.73 .mu.Uh/ml; 554.+-.84 .mu.Uh/ml; and
530.+-.81 .mu.Uh/ml [3024.+-.438, 3324.+-.504, 3180.+-.486 pmol/L],
respectively) (FIG. 4, insets). It was decreased at five weeks on
the test diet (318.+-.39 .mu.Uh/ml) (1908.+-.702 pmol/L). This was
a decrease of 40% from the pre-test value (p<0.01) (FIG. 4,
insets). The mean 24-hour total integrated insulin area response
decreased by 25%.
[0062] The mean fasting C-peptide concentration before and after
the control diet was 0.86.+-.0.08 and 0.91.+-.0.08 pg/ml, and
0.81.+-.0.09 and 0.92.+-.0.08 before and after the test diet. The
24-hour time course response was similar to the insulin response.
The net C-peptide area response was decreased by 34% after 5 weeks
on the test diet. This was statistically significant
(p<0.05).
[0063] The mean total glycohemoglobin was essentially unchanged
during the 5 weeks on the control diet (FIG. 5). A decrease in
total glycohemoglobin was present 1 week after the institution of
the test diet, and became significant after 3 weeks on the test
diet. At the end of the 5-week period, the total glycohemoglobin
had decreased 22%, from 9.8.+-.0.5% to 7.6.+-.0.3%
(p<0.0007).
[0064] The mean fasting glucagon concentrations were similar before
and after both the control and test diets (95.+-.11, 91.+-.8,
91.+-.7, and 94.+-.7 pg/ml, respectively) (FIGS. 6A and 6B). After
5 weeks on the test diet, the glucagon response was similar to the
control for the first hour after breakfast. Subsequently, the
glucagon concentration was higher at every time point until 0700 hr
the following morning, except for one time point after dinner. Both
the net and the total glucagon area responses were significantly
increased after the test diet (p<0.05) (FIG. 6, insets).
[0065] The mean fasting NEFA concentrations were 765.+-.67,
654.+-.59, 718.+-.70 and 593.+-.50 .mu.Eq/l, before and after the
control and test diets, respectively. These differences were not
statistically significant p>0.05). The 24-hour excursions were
similar on the pre-control and pre-test diet days. When the test
diet was ingested, the fasting NEFA was lower, the increase after
the lunch meal was attenuated, as was the decrease before dinner.
The rise after dinner was more rapid and reached a higher
concentration.
[0066] The mean 24-hr integrated net NEFA area responses were
(-)5323.+-.1187, (-)2468.+-.693, (-)4525.+-.1660 and 80.+-.1809
.mu.Eq hr/l before and after the control and test diets,
respectively. The small positive area response after the test diet
was statistically significantly different compared to the response
before the test diet (p<0.05). Total areas were not
statistically different from one another.
[0067] The mean fasting triacylglycerol concentrations were
264.+-.36, 226.+-.32, 246.+-.27 and 149.+-.23 mg/dl before the
after the control and test diets, respectively. The fasting
triacylglycerol concentration was significantly lower after 5 weeks
on the test diet (p<0.05). After ingestion of either diet, the
triacylglycerol concentration increased until .about.1200-1400 h,
decreased at 2000-2200 h, increased slightly at .about.2400 h and
subsequently returned to the fasting value by 0800 h the following
morning.
[0068] The mean 24-h integrated net triacylglycerol area response
was not significantly different between diets. However, the mean
24-h integrated total area response was significantly lower after 5
weeks on the test diet (p<0.05) (FIG. 7, insets).
[0069] The total cholesterol concentrations were 195.+-.7,
184.+-.17, 188.+-.10 and 177.+-.8 mg/dl before and after the
control and test diets, respectively. The LDL-cholesterol
concentrations were 105.+-.9, 102.+-.2, 105.+-.7, and 110.+-.6
mg/dl before and after the control and test diets, respectively.
The HDL-cholesterol concentrations were 38.+-.1, 37.+-.2, 37.+-.2,
and 36.+-.2 before and after the control and test diets,
respectively. The total, LDL, and HDL concentrations were not
significantly different between diets or before and after each
diet.
[0070] The serum total, LDL, and HDL cholesterol concentrations did
not change significantly when the fat content of the diet was
increased from 30% to 50% of total food energy. This was most
likely due to the saturated fatty acid content being kept at 10% of
energy in both diets. The test diet dramatically reduced 24-hour
integrated glucose concentration and consequently the percent
glycohemoglobin in people with type 2 diabetes. These positive
results occur without a significant change in serum lipids, except
for a significant decrease in triacylglycerol concentration.
Example 6
Results #2
[0071] The plasma .alpha.-amino nitrogen (AAN) concentration
increased after meals, as expected. When the meals contained 15%
protein (control diet), the AAN concentration increased with each
meal but decreased to near basal levels between meals. However,
when the diet contained 30% protein (Diet.sub.20), only modest
decreases were measured after breakfast and lunch. The AAN
concentration did return to the fasting concentration overnight in
all cases. The increase in AAN after the dinner meal in the
control/pre is unexplained.
[0072] The net area response integrated over 24 hours using the
fasting value as baseline were 2.6, 3.6, 4.8 and 15 mghr/dl in the
control/pre, control/post, Diet.sub.20/pre and Diet.sub.20/post
diets, respectively. Thus, the area response was .about.3 fold
greater after ingestion of the Diet.sub.20, which contained twice
as much protein (p<0.05). When the total area was calculated
using zero as a baseline, the response to the Diet.sub.20 again was
significantly greater (p<0.05).
[0073] The fasting plasma urea nitrogen was 14-15 mg/dl before and
after the control diet and before instituting the Diet.sub.20. At
the end of the 5-week period on the Diet.sub.20, it had increased
to 22 mg/dl. Thus, the Diet.sub.20 at 30% protein resulted in a 57%
increase in fasting plasma urea nitrogen. A gradual further small
increase in urea nitrogen occurred throughout the day while
ingesting the Diet.sub.20, until the 17-hour time point, after
which the concentration decreased to 21 mg/dl by the following
morning. This late evening increase in concentration was nearly
identical to that reported previously in subjects who ingested a
30% protein, 40% carbohydrate, 30% fat diet (Diet.sub.40). The
total urea nitrogen area response, using zero as baseline, was 45%
greater (p<0.05) after ingestion of the Diet.sub.20.
[0074] The calculated total amount of protein ingested during the
24-hour study period was compared with the total protein
metabolized. After ingestion of the 15% protein meals (control),
106 g of protein were calculated to have been ingested and 92 g
were calculated to have been metabolized (87%). After ingestion of
the 30% protein meals (Diet.sub.20), 212 g of protein were
calculated to have been ingested and 142 g were calculated to have
been metabolized (67%). This difference was statistically
significant (p<0.03).
[0075] Serum growth hormone concentrations did not differ
significantly between treatments. The serum IGF-1 concentration was
similar before and after ingestion of the control diet and before
ingestion of the Diet.sub.20. However, it increased significantly
from a mean of 115 to 161 ng/ml after 5 weeks on the Diet.sub.20
(p<0.01).
[0076] Plasma renin activity was determined in 7 subjects. There
was a mean increase when the subjects ingested the control diet.
After institution of the Diet.sub.20, plasma rennin activity
decreased (Table 4). These differences were not statistically
significantly different (p=0.13 and 0.20, respectively).
[0077] Mean 24-hour urinary aldosterone excretion was not different
between diets. The mean urinary free cortisol was obtained in only
6 subjects. Mean urinary free cortisol increased by 44% consequent
to the ingestion of the Diet.sub.20, but this was not statistically
significant (p=0.17).
[0078] Neither the serum TSH, free T4, nor the Total T3 were
significantly affected by ingestion of the Diet.sub.20, even though
the Diet.sub.20 contained much less carbohydrate than the control
diet (Table 4).
[0079] Blood pressure remained unchanged. Serum homocysteine,
folate and B12 also remained unchanged (Table 4). Urinary
.beta.-hydroxybutyrate excretion did not increase, nor did the
urinary pH change when the subjects ingested the Diet.sub.20 (Table
5). The creatinine clearance and microalbumin excretion also did
not change. Sodium excretion was increased. The 24-hour urinary
urea nitrogen increased when the subjects ingested the Diet.sub.20.
However, the mean increase was only .about.60%, and not 2-fold as
might be expected with a doubling of the protein content in the
diet. TABLE-US-00004 TABLE 4 Blood pressure, plasma/serum hormones,
vitamins & metabolites Control-Pre Control-Post Diet.sub.20-Pre
Diet.sub.20-Post Blood Pressure (mm Hg) 133/77 127/72 146/76 133/74
Serum Creatinine (mg/dl) 0.9 .+-. 0.1 0.9 .+-. 0.05 0.9 .+-. 0.05
1.0 .+-. 0.05* Renin (ng/ml) 0.64 .+-. 0.3 1.03 .+-. 0.3 0.69 .+-.
0.1 0.47 .+-. 0.1 Serum Uric Acid (mg/dl) 4.9 .+-. 0.2 5.5 .+-.
0.03 5.3 .+-. 0.3 5.8 .+-. 0.3 TSH (.mu.IU/ml) 1.60 .+-. 0.22 1.49
.+-. 0.16 1.50 .+-. 0.13 1.39 .+-. 0.16 Total T.sub.3 (ng/dl) 83.3
.+-. 8.5 79.6 .+-. 7.3 86.9 .+-. 7.9 81.9 .+-. 6.9 Free T.sub.4
(ng/dl) 0.90 .+-. 0.04 0.85 .+-. 0.02 0.98 .+-. 0.05 1.04 .+-. 0.03
Folate (ng/ml) 16.5 .+-. 2.3 20.2 .+-. 1.2 18.0 .+-. 2.1 15.8 .+-.
2.2 Homocysteine (.mu.g/dl) 8.1 .+-. 0.7 8.1 .+-. 0.8 8.9 .+-. 1.1
7.8 .+-. 2.1 B.sub.12 (pg/ml) 524 .+-. 119 496 .+-. 99 557 .+-. 120
475 .+-. 108 Values are Mean .+-. SEM *p < 0.02 compared to
Diet.sub.20-Pre
[0080] TABLE-US-00005 TABLE 5 Urine data Control-Pre Control-Post
Diet.sub.20-Pre Diet.sub.20-Post Volume (ml) 4129 .+-. 707 3961
.+-. 691 4366 .+-. 502 4127 .+-. 558 Glucose (g) 22 .+-. 8 14 .+-.
4 17 .+-. 9 0.3 .+-. 0.3 Potassium (mg) 3315 .+-. 254 3471 .+-. 312
3471 .+-. 250 3081 .+-. 156 Sodium (mg) 5451 .+-. 276 5451 .+-. 713
4692 .+-. 253 6923 .+-. 759* Urea (g) 12.2 .+-. 0.9 13.3 .+-. 1.0
12.8 .+-. 0.9 20.6 .+-. 1.4* Uric Acid (g) 0.84 .+-. 0.12 0.72 .+-.
0.06 0.78 .+-. 0.11 0.90 .+-. 0.09.dagger. Micro albumin (mg) N/A
9.7 .+-. 1.7 N/A 8.3 .+-. 1.1 .beta.-OH butyrate (.mu.M) 187 .+-. 7
203 .+-. 10 196 .+-. 8 196 .+-. 8 Calcium (g) 220 .+-. 52 217 .+-.
62 221 .+-. 62 214 .+-. 64 pH 6.3 .+-. 0.1 6.2 .+-. 0.1 6.1 .+-.
0.1 6.2 .+-. 0.1 Creatinine (g) 1.8 .+-. 0.15 1.7 .+-. 0.13 1.8
.+-. 0.13 1.8 .+-. 0.15 Creatinine clearance (ml/min) 143 .+-. 51
127 .+-. 45 144 .+-. 51 137 .+-. 48 Values are mean .+-. SEM *p
< 0.05 compared to Diet.sub.20-Pre .dagger.p = 0.06 compared to
Diet.sub.20-Pre
B. Diet.sub.30
Example 1
Participants
[0081] Eight men with mild, untreated type 2 diabetes were studied
in a special diagnostic and treatment unit (SDTU), similar to a
clinical research center. All participants met the National
Diabetes Data Group criteria for the diagnosis of type 2 diabetes
and were not being treated with oral hypoglycemic agents or
insulin. Participant characteristics are given in Table 6. The
Department of Veterans Affairs Medical Center and the University of
Minnesota Committees on Human Subjects approved the study, and all
participants gave written informed consent prior to enrollment in
the study. Exclusion criteria included: hematological
abnormalities, kidney disease, liver disease, macroalbuminuria
(>300 mg/24 h), congestive heart failure, or untreated thyroid
disease. before the study, participants were interviewed to
determine their physical activity profile, any food aversions and
to explain the study process and commitment in detail. Participants
confirmed that they had been weight stable for at least 3 months.
They were instructed to maintain their current activity level
throughout the study. Two weeks before beginning the study, the
participants completed a 3-day food questionnaire, with one of the
days being a Saturday or a Sunday. This information was used to
calculate the total food energy necessary to maintain body weight.
TABLE-US-00006 TABLE 6 Patient characteristics Duration of Age
Height Weight BMI tGHb diabetes Patient (yrs) (cm) (kg)
(kg/m.sup.2) (%) (months) Concomitant diseases Medications 1 50 175
97 32 10.0 42 hypertension, bupropion, hypercholesterolemia,
clonazepam, multiple sclerosis, cyclobenzapine, major depressive
gabapentin, disorder, trigeminal glatiramer neuralgia acetate,
nifedipine, sertraline 2 64 178 75 24 11.2 48 hypertension, none
traumatic brain injury 3 52 173 85 29 8.7 24 none aspirin 4 67 183
92 28 11.0 180 hypertension none 5 57 185 120 35 11.2 36
dyslipidemia none 6 56 180 89 27 11.4 72 seizure disorder, post-
aspirin, traumatic stress phenytoin disorder 7 64 185 110 32 9.9
132 hypertension, Atorvastatin, hypercholesterolemia lisinopril 8
62 175 82 27 12.7 66 dyslipidemia, GERD Simvastatin, ranitidine
Mean 59 179 94 29 10.8 75 -- -- Range 50-67 173-185 75-120 24-35
8.7-12.7 24-180 -- --
Example 2
Diet
[0082] The study diet was designed to consist of 30% carbohydrate,
30% protein, and 40% fat. The saturated fatty acid content of the
diet was approximately 10% of total food energy; thus, the majority
of the fat was mono- and polyunsaturated. This diet is referred to
as Diet.sub.30. The diet composition of the Diet.sub.30 is given in
Table 7 and representative meals are shown in Table 8. Each patient
was on the six-day rotation for a total of five weeks.
TABLE-US-00007 TABLE 7 Composition of Diet.sub.30 Protein (g) 158
Carbohydrates (g) 155 Fat (g) 94 Cholesterol (mg) 450 Dietary fiber
(g) 20 Saturated fat 12% Monounsaturated fat 16% Polyunsaturated
fat 12% Calories 2109
[0083] TABLE-US-00008 TABLE 8 Sample Menu of Diet.sub.30 Breakfast
Omelet: 4 ounces egg substitute 2 ounces cheddar cheese 2 slices
bacon 1 green onion 1/4 green pepper 2 slices pineapple Lunch
Chef's salad: 1 hard cooked egg 2 ounces extra lean ham 2 ounces
white turkey 1/3 cup celery 6 slices cucumber 11/2 cups lettuce 1
ounce lite cheese 2 Tbsp Italian dressing 1/4 cup water chestnuts 3
rye krisp wafers 1 tsp Fleishman's soft margarine Supper 8 ounces
broiled cod 1 cup asparagus raw carrots and celery sticks 1 T Ranch
dressing 1/2 cup brown rice 1 banana Snack 2 ounces cottage cheese
2 halves peaches 2 ounces peanuts
Example 3
Experimental Plan
[0084] Participants were admitted to the SDTU on the evening prior
to the study. The next day, standardized meals containing 55%
carbohydrate, 30% fat, and 15% protein (control diet) were given
for breakfast, lunch and dinner at 0800, 1200, and 1800.
Participants were asked to remain in the SDTU during the study
period with minimal activity.
[0085] On the second day in the SDTU, standardized meals again were
given. In addition to the meals at 0800, 1200 and 1800, snacks were
given at 1600 and 2100. Fasting blood was obtained at 0730, 0745,
and 0800. Then samples were collected every 15 min for the first
hour after meals, every 30 min for the next 2 h, and then hourly
until the next meal. Blood was drawn at a total of 46 time points.
After this 24-h data accumulation period, the participants were
sent home with all of the necessary food for the next 2-3 days
according to the Diet.sub.30 menu plan.
[0086] Participants returned to the SDTU every 2-3 days to pick up
food and meet with the study dietitian and study coordinator. At
that time, the subjects provided a urine specimen for analysis of
creatinine and urea to determine dietary compliance. They also were
weighed and had blood pressure, total glycohemoglobin (tGHb), and
blood glucose measured. If their body weight decreased or increased
on two successive occasions, the total food energy of the meals was
increased or decreased as appropriate to attempt to maintain stable
weight throughout the study. In addition, participants were
interviewed regarding dietary compliance during each visit. At the
end of the 5-week period, the participants again were admitted to
the SDTU and blood was drawn as described above. At this time,
participants were given the meals (breakfast, lunch, dinner, and
snacks) as appropriate for the day in the Diet.sub.30 menu
rotation.
Example 4
Biological Measurements
[0087] The plasma glucose concentration, HDL cholesterol, and total
cholesterol were measured with the use of an automated method on an
Ortho-Clinical Diagnostics Vitros 950 analyzer (Raritan, N.J.). LDL
cholesterol was calculated with the Fridedwald Formulation. The
.beta.-hydroxybutyrate concentration was determined by colormetric
assay (STANBIO, Boerne, Tex.). % tGHb was measured by
boronate-affinity high-performance liquid chromatography (BioRad
Variant; BioRad Labs, Hercules, Calif.). Serum immunoreactive
insulin was measured using standard double-antibody
radioimmunoassay kits from Incstar (Stillwater, Minn.). Glucagon
and C-peptide were measured with radioimmunoassay kits from Linco
Research (St. Louis, Mo.) and Diasorin (Stillwater, Minn.),
respectively. Weight was determined in street clothes without shoes
on a digital scale (Scalitronix, White Plains, N.Y.). Blood
pressure was measured using a Dinemap instrument (Critikon/Mediq,
Pennsauken, N.J.).
[0088] The plasma creatinine, plasma urea nitrogen, uric acid were
measured with the use of an automated method on an Ortho-Clinical
Diagnostics Vitros 950 analyzer (Raritan, N.J.). NEFAs were
measured enzymatically using a kit manufactured by Wako Chemicals
(Richmond, Va.).
[0089] The net 24-h incremental area responses were calculated
using the overnight fasting value as baseline. Total 24-h area
responses were calculated using zero as the baseline. Both area
calculations were done using a computer program based on the
trapezoid rule. Statistics were determined using Student's t test
for paired variates, with the Statview 512+ program (Brain Power,
Calabasas, Calif.) for the Macintosh computer (Apple Computer,
Cupertino, Calif.). P<0.05 is the criterion for significance.
Data are presented as the mean.+-.SE. Prospective power
calculation, with .beta. equal to 90%, resulted in n=3.
Example 5
Results #1
[0090] The average body weight was 206.+-.11.3 lb (94.+-.5.1 kg)
before the diet. At the end of the 5 weeks on the diet, the average
weight was essentially unchanged 204.+-.11.2 lb (93.+-.5.1 kg).
[0091] Urine ketones were monitored twice weekly while participants
were on the Diet.sub.30. The majority of the samples were zero to
trace using nitroprusside impregnated tablets (Bayer, Elkhart,
Ind.); two single samples were positive for ketones.
[0092] The total area of the 24-h plasma .beta.-hydroxybutyrate
data was modestly higher after the Diet.sub.30 but not
significantly.
[0093] The mean fasting plasma glucose concentration decreased
significantly from 227.+-.18.6 mg/dl (12.6.+-.1 mmol/L) to
130.+-.14.3 mg/dl (7.2.+-.0.79 mmol/L; P=0.001) after 5 weeks on
the die). The mean 24-h integrated net glucose area response
decreased from 1269.+-.269 mghr/dl (70.5.+-.14.9 .mu.molhr/L) to
449.+-.129 mghr/dl (24.9.+-.7.2 .mu.molhr/L) (P=0.001). The total
area response decreased from 6717.+-.501 mghr/dl (373.+-.27.8
.mu.molhr/L) to 3724.+-.348 mghr/dl (207.+-.19.3 .mu.molhr/L;
P=0.0001).
[0094] The mean fasting serum insulin concentration was unchanged
(8.4.+-.1.1 .mu.U/ml (50.4.+-.6.6 pmol/L) and 9.0.+-.1.0 .mu.U/ml
(54.+-.6 pmol/L)) before and after 5 weeks on the diet,
respectively. The mean 24-h integrated net insulin area response
and the total integrated insulin area response also remained
essentially unchanged after 5 weeks on the diet.
[0095] The mean fasting serum C-peptide concentration also was
unchanged after 5 weeks on the diet (0.6.+-.0.1 ng/ml to 0.8.+-.0.2
ng/ml, P=0.3). The 24-h time course response was similar to the
insulin response. The net C-peptide area response decreased from
11.4.+-.2.4 nghr/ml to 10.6.+-.1.4 ng.about.hr/ml after 5 weeks on
the Diet.sub.30. This was not statistically significant
(P>0.05). The 24-h total area did not change before or after the
diet, 25.+-.2.9 nghr/ml to 25.8.+-.2.54 nghr/ml respectively.
[0096] The mean % tGHB decreased from 10.8.+-.0.4% to 9.1.+-.0.5%,
before and after the diet respectively (P<0.0001). In addition,
at the end of the study, it was still decreasing in an essentially
linear fashion.
[0097] The mean fasting plasma glucagon concentrations were similar
before and after the diet; 76.+-.3.1 pg/ml and 77.+-.11.1 pg/ml,
respectively. Both the 24-1 integrated net response and the 24-h
total area response increased after 5 weeks on the diet. These were
not statistically significant (P=0.33 and P=0.32,
respectively).
[0098] The mean fasting plasma triacylglycerol concentration
significantly decreased from 190.+-.24.5 mg/dl to 113.+-.9.4 mg/dl
after 5 weeks on the diet (P=0.007); however the decrease seen with
the 24-h net area was not statistically significantly. The 24-h
total area response significantly decreased from 5695.+-.806
mghr/ml to 3586.+-.326 mghr/ml (P=0.008). The total cholesterol
concentration significantly decreased from 189 mg/dl to 152 mg/dl
after 5 weeks on the diet (P=0.004). The plasma LDL and HDL
concentration decreased from 113 to 95 and from 37 to 34,
respectively, which was not significant.
Example 6
Results #2
[0099] The mean fasting NEFA concentrations decreased from
691.+-.74.6 .mu.Eq/L to 622.+-.54.8 .mu.Eq/L. This was not
statistically significant (P>0.05). The mean 24-h integrated net
NEFA area response was increased after 5 weeks on the Diet.sub.30,
however this was not significant (P>0.05). Differences in the
24-h total areas were also not statistically significant.
[0100] The mean fasting alpha amino acid nitrogen concentration was
4.01.+-.0.1 mg/dl before the diet and remained unchanged after 5
weeks on the diet. The 24-h integrated net and 24-h total area
responses were significantly increased after 5-weeks on the
Diet.sub.30.
[0101] The mean fasting plasma creatinine level remained unchanged,
0.9 mg/dl and 0.9 mg/dl, before and after the diet respectively.
However, the mean 24-h integrated net creatinine response increased
from 0.3.+-.0.3 mghr/dl to 1.7.+-.0.5 mghr/dl (P=0.768). This
difference was also present when correcting for the baseline with
the 24-h total area response.
[0102] The mean fasting uric acid concentration increased from
4.7.+-.0.4 mg/dl to 5.5.+-.0.4 mg/dl (P=0.002) and remained
elevated throughout the 24-h study period. The 24-h net area
decreased modestly after 5 weeks on the diet (P=0.9). However, the
24-h integrated total area significantly increased from 106.+-.9.6
mghr/dl to 124.+-.8.2 mghr/dl (P=0.0013).
[0103] The mean fasting plasma urea nitrogen concentration
increased from 15.+-.1 mg/dl to 19.+-.1.8 mg/dl after 5 weeks on
the diet (P<0.05). The 24-h net area response increased from
-4.+-.7.1 mghr/ml to 28.+-.11.7 mghr/ml; however this was not
significant (P=0.09). The 24-h integrated total area increased from
346.+-.22 mg/dl to 479.+-.42 mg/dl (P=0.0038).
OTHER EMBODIMENTS
[0104] It is to be understood that while the invention has been
described in conjunction with the detailed description thereof, the
foregoing description is intended to illustrate and not limit the
scope of the invention, which is defined by the scope of the
appended claims. Other aspects, advantages, and modifications are
within the scope of the following claims.
* * * * *